Albumin makes up about 62 percent of the total protein of human plasma, about 80 percent of the plasma colloidal pressure, and has been used since World War II, and continues to be used, in maintaining or restoring human plasma volume. The Standard Army and Navy Package of Dried Plasma is bulky, and therefore concentrated human serum albumin was developed to meet the needs of such groups for a concentrated blood derivative. Serum albumin has at least two known functions: it maintains the colloidal osmotic pressure of the blood and plays a role in the nutrition of the tissues. Neither plasma nor albumin solutions, however, can act as a total replacement for human blood indefinitely since they cannot supply the necessary hemoglobin and other essential blood protein constituents. However, human serum albumin is used effectively in concentrations up to about 25% by volume, and has advantages over solutions of salts and glucose in establishing safe osmotic pressure, particularly in emergency blood loss situations, e.g., in the treatment of shock hemorrhage, and other conditions associated with substantial blood loss.
Advantageously, human serum albumin can be dried to reduce volume and can be reconstituted, preferably with sterile water, prior to administration, e.g., by injection. Human serum albumin is available, for example, in 100 c.c. bottles containing 25 gm. of albumin, which is equivalent in osmotic effect to 500 c.c. of citrated plasma. Human serum albumin also is available from Bayer Healthcare, as PLASBUMIN®-25, in 20 ml. vials. PLASBUMIN®-25 is made from pooled human venous plasma using the Cohn cold ethanol fractionation process to produce a sterile solution of albumin in an aqueous diluent that is stabilized with 0.02M sodium caprylate and 0.02M acetylptophan. The approximate sodium content is 145 mEq./L., contains no preservative, and is administered intravenously.
Albumin solutions are stable, permitting transportation without refrigeration, ready for instant use, and, as with plasma, no preliminary cross-matching is necessary. A 25% w/v aqueous solution of albumin is approximately isoviscous with whole blood.
It has long been recognized in clinical medicine that an acceptable oxygen carrying and releasing resuscitation product is needed. There is currently no satisfactory non-blood product with these properties in clinical use.
Two general approaches to making such an oxygen-carrying product have been attempted either through the use of oxygen binding hemoglobin or the use of a nonpolar, fat-soluble, hydrophobic solvent system.
A third approach, that of using an aqueous system as an oxygen carrying solvent would presumably be obviated by the fact that the oxygen molecule is less than 2% soluble at physiologic temperatures in an electrolytic aqueous system such as human serum.
In the case of the hemoglobin systems the use of naked hemoglobin is toxic. Polymerized hemoglobin and hemoglobin bound to various bases, such as starch or other polymers, have proven both unstable and ineffective.
Efforts to encapsulate hemoglobin have been attempted using coacervates and liposomes. During the processing and use of liposomes the hemoglobin tends to leak from the encapsulating liposome. The liberated free hemoglobin results in the known toxicities of naked hemoglobin. Additionally, the hemoglobin that remains in the liposome does not release oxygen in the patient as needed. Some 30 years of efforts in this direction have proven unsatisfactory. The use of liposome or polymerized hemoglobin after years of trials has not been shown to be clinically useful.
The use of coacervates containing hemoglobin demonstrated both manufacturing and clinical problems. Manufacturing efforts resulted in difficulties with achieving appropriate particle sizes and with methemoglobin formation. While the toxicities of naked hemoglobin were overcome, the resultant product had difficulties carrying and releasing oxygen in a clinically effective manner.
A nonpolar solvent system can dissolve nonpolar oxygen molecules. Many such products over the past sixty years, such as the perfluorocarbons, while effective at dissolving oxygen, have clinically proven to be toxic, unstable, and ineffective. Indeed, toxicity could be anticipated from such nonpolar systems, since many of the organs in the body are nonpolar themselves. Thus the tactic of infusing large volumes of the perfluorocarbon-type nonpolar solvent systems for carrying oxygen would tend to be absorbed by and disrupt the body's organs. A typical example is that the liver, which is nonpolar in character, absorbs the perfluorocarbon with resultant hepatomegaly and liver failure. The nonpolar solvents cannot dissolve polar drugs or vitamins or other desirable polar chemical agents.
The principal users of human serum albumin are surgeons. The indications for prescribing albumin include acute hypovolemia associated with surgery, trauma, hypoproteinemia, with or without edema, adult respiratory distress syndrome (ARDS), transplantations; obligatory extracellular space imbalance, as in severe burns, respiratory distress syndrome, and heart-lung machine pump priming. In coronary artery bypass surgery, the heart-lung machine is primed without the use of blood by using 1,000 c.c. of Ringer's lactate solution, 300 c.c. of 25% salt-poor albumin, 66.7 mEq. sodium bicarbonate or 250 c.c. trishydroxy-methyl-aminomethane, and 20 gm. of mannitol. Indications for use of human serum albumin by internists include acute gastrointestinal hemorrhage, renal dialysis, erythrocyte resuspension, sequestration of protein-rich fluids and several chronic conditions such as malabsorption, cirrhosis, acute liver failure, nephrosis, neonatal hemolytic disease, cerebral vascular accidents and ischemia.
The oxygenated albumin described herein preferably is oxygenated human serum albumin, and is more useful than non-oxygenated human serum albumin in the treatment of all of the above recited indications for prescribing albumin. The oxygenated albumin can be delivered to the human body either as a solution, or as a suspension of oxygenated albumin in sterile water.
The compositions and methods described herein stem from the unexpected finding that aqueous solutions containing up to 25% w/v concentrated amounts of hydrophilic albumin can indeed act as nonpolar solvents for delivery of oxygen and other nonpolar compounds. The most clinically useful example of this is the fact that aqueous human albumin solutions of less than 3% w/v can carry very little oxygen. However, at concentrations of around 25% w/v, human albumin in water can dissolve clinically significant quantities of oxygen. Further, as the aqueous albumin solution dilutes in the blood stream, it releases the oxygen in a manner similar to that displayed by whole human blood. No hemoglobin is required in this preparation. No other solvent system exhibits these properties except whole blood.
U.S. Pat. No. 6,777,052 discloses a plastic container for containing albumin solution having an albumin concentration of 1 to 500 mg/ml. The oxygenated albumin solutions described herein can be used with such a container in oxygenated albumin concentrations of 1 to 500 mg/ml, or any other oxygen-impermeable package, e.g., glass bottles, can be used to contain the oxygenated albumin compositions described herein.